Most Damaging Clinical Trial Failure: AstraZeneca's MYSTIC
AstraZeneca's MYSTIC study
PD-L1 expression cutoff:
A combo flop:
The PD-L1 inhibitor Imfinzi, when combined with the CTLA-4 blocker tremelimumab, failed to improve PFS in first-line NSCLC patients.
AstraZeneca's stock dropped 15% the day MYSTIC was announced, closing at $28.88 per share.
Overall survival data from MYSTIC, expected next year, and results from the PACIFIC study could still help Imfinzi gain an approval in lung cancer.
While AstraZeneca plc knew its PD-L1 inhibitor Imfinzi (durvalumab) would be a late entry to the space, the company was counting on strong data in first-line non-small cell lung cancer (NSCLC) to make it a real competitor to market leaders: Merck & Co.'s Keytruda (pembrolizumab), and Bristol-Myers Squibb Co.'s Opdivo (nivolumab).
Unfortunately for the British pharma, those plans hit a major setback when the Phase 3 MYSTIC trial blew up in late July.
The study tested a pairing of Imfinzi with AstraZeneca's experimental CTLA4 inhibitor tremelimumab, but failed to show a progression-free survival benefit in first-line treatment of metastatic NSCLC patients. Adding to the disappointment, Imfinizi monotherapy also would not have beaten out standard-of-care treatment, the company said — although that secondary endpoint was not formally tested.
What makes the MYSTIC failure such a big deal?
Let's start with the build up. The company's share price was making a slow and steady climb in anticipation of the results — rising from about £46 per share in early May to a high just above £55 apiece in late June. (Roughly around the mark of Pfizer's final takeout offer in 2014, for what it's worth.)
But if you look at AstraZeneca's stock, it's clear that early July was when investors started to get nervous that MYSTIC might not succeed. This was compounded further by rumors CEO Pascal Soriot might jump ship to beleaguered generic drugmaker Teva Pharmaceuticals Co. Ltd. ahead of negative results.
A MYSTIC stumble for AstraZeneca
Once disclosed, the failure sent shares spiraling, shedding 15% in value in a matter of hours after the MYSTIC results were announced. It's not often that a big pharma stock will move that much that quickly. Big pharmas, with diversified revenue streams, tend to be shaken less by events like these, unlike their biotech counterparts which can see wild swings in share price from the smallest of catalysts.
But it wasn't just the market reaction; it was the size of the missed opportunity. Lung cancer is by far the biggest cancer market in the U.S. for checkpoint inhibitors. According to the National Cancer Institute, there are more than 222,000 cases of lung cancer diagnosed every year. That's a stark contrast to the 79,000 cases of bladder cancer seen annually — where Imfinzi is currently approved for a subset of patients.
Cancer types, by U.S. prevalence
While the hit to the stock and diminished prospects in lung cancer were both major blows, the biggest disappointment was that Imfinzi failed as a monotherapy and in combination.
Most experts in the field will point to combination therapy as the next step for immuno-oncology.This belief is the reason nearly every company in the oncology space is currently testing their drugs with a basket of drugs from other drugmakers. The idea is that certain combinations will work for different patient populations and it's just a matter of finding the right pairing.
MYSTIC, though, not only diminished the prospects for Imfinzi, but also that of tremelimumab too, putting a wrench in the British pharma's combo therapy strategy.
AstraZeneca really needs a win. The company has been selling off assets in hopes of boosting revenues and getting close to CEO Pascal Soriot's promise of $45 billion in annual sales by 2023. Yet, sales continue to decline at the company and it doesn't appear Imfinzi will be that magic boost AstraZeneca needs.
AstraZeneca still has a chance to grab a piece of the lung cancer pie. Results from the PACIFIC study show Imfinzi cut the risk of disease progression in earlier-stage NSCLC patients for whom surgery isn't an option — a market where AstraZeneca could carve out a niche.
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